Long-term persistence and function of hematopoietic stem cell-derived chimeric antigen receptor T cells in a nonhuman primate model of HIV/AIDS.

Anjie Zhen,Valerie K Rezek,Jonathan W Rick,Irvin S Y Chen,Jerome A Zack,Masakazu Kamata,Nick C Neel,Nelson Y Chang,Brianna B Lam,Heather A Martin,Jennifer Kim,Christopher W Peterson,Cindy S Youn,Sowmya Somashekar Reddy,Hans-Peter Kiem,Scott G Kitchen,Mayra A Carrillo

doi:10.1371/journal.ppat.1006753

Abstract

Chimeric Antigen Receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer and show promise in treating HIV-1 infection. However, significant limitations are persistence and whether peripheral T cell-based products can respond to malignant or infected cells that may reappear months or years after treatment remains unclear. Hematopoietic Stem/Progenitor Cells (HSPCs) are capable of long-term engraftment and have the potential to overcome these limitations. Here, we report the use of a protective CD4 chimeric antigen receptor (C46CD4CAR) to redirect HSPC-derived T-cells against simian/human immunodeficiency virus (SHIV) infection in pigtail macaques. CAR-containing cells persisted for more than 2 years without any measurable toxicity and were capable of multilineage engraftment. Combination antiretroviral therapy (cART) treatment followed by cART withdrawal resulted in lower viral rebound in CAR animals relative to controls, and demonstrated an immune memory-like response. We found CAR-expressing cells in multiple lymphoid tissues, decreased tissue-associated SHIV RNA levels, and substantially higher CD4/CD8 ratios in the gut as compared to controls. These results show that HSPC-derived CAR T-cells are capable of long-term engraftment and immune surveillance. This study demonstrates for the first time the safety and feasibility of HSPC-based CAR therapy in a large animal preclinical model.

Highlights

HIV-1 specific cytotoxic T lymphocytes mount a key immune response to HIV and are crucial for the control of viremia and the elimination of HIV infected cells
Hematopoietic Stem/Progenitor Cells (HSPCs)-based Chimeric Antigen Receptor (CAR) therapy has several benefits over T cell gene therapy, as it allows for normal T cell development, selection, and persistence of the engineered cells for the lifetime of the patient
We used a CAR molecule that hijacks the essential interaction between the virus and the cell surface molecule CD4 to redirect HSPC-derived T-cells against infected cells

Summary

Introduction

HIV-1 specific cytotoxic T lymphocytes mount a key immune response to HIV and are crucial for the control of viremia and the elimination of HIV infected cells. CD4 CAR modified T cells can recognize and respond to HIV gp120 envelope protein on infected cells and can effectively kill HIV infected cells and limit HIV replication in vitro. Clinical trials with CD4CAR modified T cells were shown to be safe but had limited antiviral efficacy[2,3]. The lack of in vivo functionality of the transferred T cells may have been due to suboptimal T-cell handling and expansion, or because CD4CARexpressing CD8+ T-cells were susceptible to HIV infection and elimination[1,2]. Protection of the CD4CAR modified cells from viral entry is essential in order to ensure T-cell functionality and survival[4,5]

Methods

Results

Discussion

Conclusion